Vicente Morales-Oyarvide

851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital.

BACKGROUND The objective of this study was to identify trends in the diagnosis and treatment of cystic neoplasms of the pancreas using a retrospective review of patients from a surgical database at an academic referral center during a 33-year period. METHODS Patient characteristics, including demographics, pathology, and survival, were analyzed over 5 time periods between 1978 and 2011. RESULTS A total of 851 consecutive patients underwent resection for a cystic neoplasm of the pancreas during a 33-year period. Sixty-five percent of patients were female, and mean age was 60 years. The most common pathologic diagnoses were intraductal papillary mucinous neoplasm (38%), mucinous cystic neoplasm (23%), serous cystadenoma (16%), and cystic neuroendocrine neoplasm (7%). There was a stepwise increase in the number of resections across time periods (67 between 1978 and 1989; 376 between 2005 and 2011), with a parallel increase in the proportion of incidentally discovered lesions (22% to 50%). Diagnosis of intraductal papillary mucinous neoplasm was very uncommon in the first 2 time periods (before the first recognition of intraductal papillary mucinous neoplasm as a distinct entity) but predominated in the last 2 (41% and 49%), and cystic neuroendocrine neoplasms, which constituted 3% of the cystic neoplasms in the first time-period, now comprise more than 8% of pancreatic cystic neoplasms. The proportion of malignant neoplasms decreased over time (41% between 1978 and 1989; 12% between 2005 and 2011), reflecting probably the earlier diagnosis and treatment of premalignant neoplasms. Although operative mortality was minimal (4/849, 0.5%), the postoperative complication rate was 38%. Overall 5-year survival for all mucinous lesions was 87%. CONCLUSION Cystic neoplasms of the pancreas are being diagnosed and treated with increasing frequency. At present, most are incidentally discovered intraductal papillary mucinous neoplasms.

Evolution of the Whipple procedure at the Massachusetts General Hospital.

BACKGROUND Since Allen O. Whipple published his seminal paper in 1935, the procedure that bears his name has been performed widely throughout the world and is now a common operation in major medical centers. The goal of this study was to investigate the evolution of pancreatoduodenectomy at the Massachusetts General Hospital (MGH). METHODS We sought to identify all pancreatoduodenectomies performed at the MGH since 1935. Cases were obtained from a computerized database, hospital medical records, and the MGH historical archive. Demographics, diagnosis, intraoperative variables and short-term surgical outcomes were recorded. RESULTS The first pancreatoduodenectomy at the MGH was carried out in 1941; since then, 2,050 Whipple procedures have been performed. Pancreatic ductal adenocarcinoma was the most frequent indication (36%). Pylorus preservation has been the most important variation in technique, accounting for 45% of Whipple procedures in the 1980s; observation of frequent delayed gastric emptying after this procedure led to decline in its use. Pancreatic fistula was the most frequent complication (13%). Operative blood replacement and reoperation rates have decreased markedly over time; the most frequent indication for reoperation was intra-abdominal bleeding. Mortality has decreased from 45% to 0.8%, with sepsis and hypovolemic shock being the most frequent causes of death. Mean duration of hospital stay has decreased from >30 to 9.5 days, along with an increasing readmission rate (currently 19%). CONCLUSION The Whipple procedure in the 21st century is a well-established operation. Improvements in operative technique and perioperative care have contributed in making it a safe operation that continues evolving.

Histologic and cytomorphologic features of ALK- rearranged lung adenocarcinomas

Chromosomal rearrangements leading to constitutive activation of anaplastic lymphoma receptor tyrosine kinase (ALK) define a category of lung adenocarcinomas that may be amenable to targeted therapy with the ALK inhibitor crizotinib. Defining distinctive features of ALK-rearranged (ALK+) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of ALK+ lung adenocarcinomas are conflicting and are primarily based on analysis of resected primary lung tumors. It is unclear whether the findings from prior studies are applicable to metastatic lung tumors or to small biopsy/cytology specimens. To address these issues, we examined resection, excision, small biopsy, and cytology cell block specimens from 104 ALK+ and 215 ALK− lung adenocarcinomas from primary and metastatic sites. All cases were evaluated for ALK rearrangements by fluorescence in situ hybridization. The predominant histologic subtypes and distinctive cytomorphologic features were assessed in each case. Primary ALK+ lung adenocarcinomas showed a significant association with solid, micropapillary, and papillary-predominant histologic patterns and tumor cells with a signet ring or hepatoid cytomorphology. Among metastatic lung tumors and small biopsy/cytology specimens, the only distinguishing morphologic feature of ALK+ tumors was the presence of signet ring cells. Based on these results, we developed a morphology-based scoring system for predicting ALK rearrangements in lung adenocarcinomas. The scoring system predicted ALK rearrangements in a new cohort of 78 lung adenocarcinomas (29 ALK+ and 49 ALK−) with a sensitivity of 88% and a specificity of 45%. In conclusion, ALK+ lung adenocarcinomas have distinctive morphologic features, with signet ring cells showing a significant association with ALK rearrangements irrespective of tumor site (primary vs metastatic) or specimen type. However, morphologic screening alone will not detect a minority of ALK+ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment.

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape (adaptive immune resistance), and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. We performed immunohistochemistry for PD-L1 on 181 cases of colorectal carcinoma with known microsatellite instability and mutational status, and correlated PD-L1 expression with clinicopathologic features including tumor-infiltrating lymphocyte burden/immunophenotype, tumor mutational profile, and disease-specific survival. PD-L1 was expressed in tumors from 16 patients (9%) who were more often older (P=0.006) and female (P=0.035), with tumors exhibiting a larger size (P=0.013), but lower stage (P<0.001). PD-L1 expression was associated with increased CD8 and TBET-positive tumor-infiltrating lymphocytes, medullary phenotype, poor differentiation, microsatellite instability, BRAF mutation (P<0.001 for each), and a lower frequency of KRAS mutation (P=0.012). On multivariate analysis, PD-L1 expression was associated with medullary morphology and frequent CD8-positive tumor-infiltrating lymphocytes, suggesting adaptive immune resistance. PD-L1 positivity was not predictive of survival in the entire cohort, but it was associated with a lower disease-specific survival within the microsatellite-instability high cohort. PD-L1 expression in colorectal carcinoma is associated with clinicopathologic and molecular features of the serrated pathway of colorectal carcinogenesis, and is associated with a worse outcome within microsatellite-unstable tumors. These findings support the role of PD-L1 expression in providing normally immunogenic colorectal carcinoma a means of immune evasion and a more aggressive biology, provide a potential mechanistic explanation for the favorable response of microsatellite-unstable colorectal carcinoma to PD-1/PD-L1 pathway blockade, and suggest potential predictive and prognostic roles of PD-L1 immunohistochemistry in colorectal carcinoma.

Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients with Pancreatic Adenocarcinoma

Objective: The aim of this study was to evaluate and validate the proposed 8th edition American Joint Committee on Cancer (AJCC) system for T and N staging of pancreatic adenocarcinoma. Summary of Background Data: Investigators have questioned the clinical relevance and reproducibility of previous AJCC staging for pancreatic adenocarcinoma. Methods: Prospective databases at Memorial Sloan Kettering (MSK), Massachusetts General Hospital (MGH), and Johns Hopkins Hospital (JHH) were queried for patients who had undergone resection for pancreatic adenocarcinoma. Patients who underwent a margin-negative (R0) resection, and who had previously undergone pathologic review, were included. Patients were staged according to 7th edition AJCC criteria, as well as the proposed 8th edition system that includes different definitions of tumor size (T) and nodal status (N). The dataset was randomly split into training and test sets. Results: Two thousand three hundred eighteen patients were identified who met inclusion criteria. Recursive partitioning on the training set (n = 1551) identified statistically appropriate cutoffs for tumor size (<2.2 cm, ≥4.8 cm,) and nodal status (no positive nodes, 1 to 3 positive nodes, ≥4 positive nodes) that supported the proposed 8th edition changes. Median survival in patients staged as T3, N0 by the 7th edition definitions was different between institutions (median Center 1, 24 mo; Center 2, 37 mo; Center 3, 29 mo; P = 0.054). This difference was not observed when patients were staged as T3, N0 by 8th edition criteria. Stage, and stage-specific outcome (7th edition), on the test set revealed a predominance of patients (68%) within the IIB subgroup, and a concordance probability estimate (CPE) of 0.57 for stage-specific survival. When assessed with 8th edition criteria, no stage subgroup had a majority of patients, and the CPE was 0.58. Conclusions: The proposed 8th edition changes for T and N classification were statistically valid and may allow a more reproducible system of T staging. This system also stratifies patients more evenly across stages without sacrificing prognostic accuracy.

Tumor islands in resected early-stage lung adenocarcinomas are associated with unique clinicopathologic and molecular characteristics and worse prognosis.

Tumor islands—large collections of tumor cells isolated within alveolar spaces—can be seen in lung adenocarcinomas. Recently we observed by 3-dimensional reconstruction that these structures were connected with each other and with the main tumor in different tissue planes, raising the possibility of tumor islands being a means of extension. However, the clinical and prognostic significance of tumor islands remains unknown. In this study, we compared clinicopathologic and molecular characteristics and prognosis of stages I to II lung adenocarcinomas with tumor islands (n=58) and those without (n=203). Lung adenocarcinomas with tumor islands were more likely to occur in smokers, exhibit higher nuclear grade and a solid or micropapillary pattern of growth, and harbor KRAS mutations. In contrast, lung adenocarcinomas without tumor islands were more likely to present as minimally invasive adenocarcinoma, show a lepidic pattern of growth, and harbor EGFR mutations. Although there was no difference in stage, the prognosis of lung adenocarcinomas with tumor islands was significantly worse than those without. The 5-year recurrence-free survival for patients with tumor islands and those without was 44.6% and 74.4%, respectively (log rank P=0.010). The survival difference remained significant (P <0.020) by multivariate analysis, and the presence of tumor islands was associated with almost 2-fold increase in the risk of recurrence. Even in the stage IA cohort, more than half of the patients with tumor islands experienced recurrence within 5 years. Thus, aggressive surveillance and/or further intervention may be indicated for patients whose tumors exhibit tumor islands.

IPMN involving the main pancreatic duct: biology, epidemiology, and long-term outcomes following resection.

OBJECTIVES To describe the characteristics of intraductal papillary mucinous neoplasms (IPMNs) with predominant involvement of the main pancreatic duct (MPD), analyzing predictors for survival and recurrence. BACKGROUND IPMNs involving the MPD harbor a high likelihood of malignancy and different biological features. The appropriateness of including cases with minimal noncircumferential MPD involvement has been challenged because these show clinicopathological features that are similar to branch duct IPMN. Accordingly, their exclusion has led to a redefinition of MPD IPMN (MD-IPMN). METHODS Retrospective review of resected MD-IPMN from 1990 to 2013. All slides were reviewed by a single pancreatic pathologist and classified on the basis of epithelial type and invasive component. RESULTS A total of 223 patients underwent resection for IPMN involving the MPD. Of these, 50 were excluded because of minimal MPD involvement. Among the 173 patients analyzed, median age was 68 years and 55% were males. Predominant epithelial phenotype was intestinal (50%). Forty-eight patients (28%) had low- or intermediate-grade dysplasia, whereas 125 (72%) had either high-grade dysplasia (33%) or invasive carcinoma (39%). Of the 67 invasive IPMNs, 39 were tubular carcinomas (58%) and invasion was minimal (<5 mm) in 28 (42%). The 5-year overall survival rate was 69% and the disease-specific survival rate was 83%. The estimated recurrence rate at 10 years was 25%. Size and type of the invasive component, lymph node positivity, and a positive resection margin were predictors for both survival and recurrence (P < 0.05). CONCLUSIONS MD-IPMN is mainly intestinal-type and malignant. After resection, it has a very favorable prognosis, especially in the absence of macroscopic invasive carcinoma.

Cystic pancreatic neuroendocrine tumors: The value of cytology in preoperative diagnosis

Cystic pancreatic neuroendocrine tumors (cPanNETs) account for 13% to 17% of PanNETs. Although the value of endoscopic ultrasound (EUS) imaging and cyst fluid analysis (CFA) in their preoperative diagnosis has been well described, limited information is available about the diagnostic role of cytology samples obtained from fine‐needle aspiration (FNA).

Programmed Cell Death Ligand 1 Expression in Resected Lung Adenocarcinomas: Association with Immune Microenvironment

Introduction Programmed cell death ligand 1 (PD‐L1) expression on tumor cells can be upregulated via activation of CD8+ cytotoxic T lymphocytes (CTLs) or the T helper cell (Th1) pathway, counterbalancing the CTL/Th1 microenvironment. However, PD‐L1 expression in association with subtypes of tumor‐associated lymphocytes and molecular alterations has not been well characterized in lung adenocarcinomas. Methods PD‐L1 expression was evaluated in 261 resected lung adenocarcinomas using tissue microarrays and various scoring systems, and was correlated with clinicopathologic/molecular features, including the extent/subtype of tumor‐associated lymphocytes (i.e., CD8, T‐bet [Th1 transcription factor], and GATA3 [Th2 transcription factor]), and patient outcomes. Results PD‐L1 expression was present in 129 (49%), 95 (36.5%), and 62 (24%) cases using cutoffs of ≥1%, ≥5%, and ≥50%, respectively, 98 (38%) by H score and 72 (28%) by immune score. PD‐L1 expression was associated with abundant CD8+ and/or T‐bet+ tumor‐infiltrating lymphocytes and EGFR wild‐type, significant smoking history, and aggressive pathologic features. In addition, concurrent PD‐L1 expression and abundant CD8+ tumor‐associated lymphocytes were seen in 25% of KRAS mutants or cases with no alterations by clinical molecular testing as opposed to only 7.4% of EGFR mutants. PD‐L1 expression was significantly associated with decreased progression‐free and overall survival rates by univariate analysis, but not by multivariate analysis. Conclusion PD‐L1 expression in resected lung adenocarcinomas is frequently observed in the presence of CTL/Th1 microenvironment, in particular in those with KRAS mutations or no common molecular alterations, suggesting that blockade of the PD‐1/PD‐L1 axis may be a promising treatment strategy to reinstitute active immune response for at least a subset of such patient populations.

mAb Das-1 is specific for high-risk and malignant intraductal papillary mucinous neoplasm (IPMN)

Objective Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes that correlate with histological grades and risks for malignant transformation. mAb Das-1 is a monoclonal antibody against a colonic epithelial phenotype that is reactive to premalignant conditions of the upper GI tract. We sought to assess the ability of mAb Das-1 to identify IPMN with high risk of malignant transformation. Design mAb Das-1 reactivity was evaluated in 94 patients with IPMNs by immunohistochemistry. Lesional fluid from 38 separate patients with IPMN (n=27), low-grade non-mucinous cystic neoplasms (n=7) and pseudocysts (n=4) was analysed by ELISA and western blot. Results Immunohistochemistry—Normal pancreatic ducts were non-reactive and low-grade gastric-type IPMN (IPMN-G) (1/17) and intermediate-grade IPMN-G (1/23) were minimally reactive with mAb Das-1. In contrast, mAb Das-1 reactivity was significantly higher in high-risk/malignant lesions (p<0.0001) including: intestinal-type IPMN with intermediate-grade dysplasia (9/10); high-grade dysplasia of gastric (4/7), intestinal (12/12), oncocytic (2/2) and pancreatobiliary types (2/2); and invasive tubular (8/12), colloid (7/7) and oncocytic (2/2) carcinoma. The sensitivity and specificity of mAb Das-1 for high-risk/malignantIPMNs were 85% and 95%, respectively. Lesional fluid—Samples from low- and intermediate-grade IPMN-G (n=9), and other low-grade/benign non-mucinous lesions demonstrated little reactivity with mAb Das-1. Conversely, cyst fluid from high-risk/malignant IPMNs (n=18) expressed significantly higher reactivity (p<0.0001). The sensitivity and specificity of mAbDas-1 in detecting high-risk/malignant IPMNs were 89% and 100%, respectively. Conclusions mAb Das-1 reacts with high specificity to tissue and cyst fluid from high-risk/malignant IPMNs and thus may help in preoperative clinical risk stratification.